How Does Choice of Polymorphism Influence Estimation of LD and Mapping?

Abstract

Fine-mapping and positional cloning studies may focus on only a subset of polymorphisms identified within a region. In part this may reflect the trade-off between information and economics. For example, for many of the genetic analytic approaches commonly used in fine-mapping and positional cloning, there is little value in typing polymorphisms that are in near-perfect linkage disequilibrium (LD) with each other. Consequently, investigators may focus initially on only those polymorphisms that have unique patterns in some small subset of individuals used in screening studies. While this strategy is economical and scientifically defensible for many common analytic approaches, it precludes unbiased estimation of the extent of LD in a region. Moreover, consequences for more sophisticated multipoint LD mapping approaches considering extended haplotypes are difficult to predict. We report here on studies of the NIDDM1 region of 2qter and a region on chromosome 15 including CYP19 in which we have made a systematic examination of the effects of this type of polymorphism choice. While our conclusions are clearly limited because we have studied only these two regions, our results suggest that multipoint linkage disequilibrium mapping methods can be sensitive to choice of polymorphism. In contrast, studies on the extent of LD in a region may be less sensitive to this type of polymorphism choice, as long as all common polymorphisms with unique patterns are included in analyses.